Involvement of endogenous N-methyl(R) salsolinol in Parkinson's disease: induction of apoptosis and protection by (-)deprenyl

An endogenous dopamine-derived N-methyl(R)salsolinol has been suggested to be involved in the pathogenesis of Parkinson's disease. In Parkinson's dise ase, the level of N-methyl(R)salsolinol increased in cerebrospinal fluid an d the high activity of a synthesizing enzyme, (R)salsolinol N-methyltransfe rase, was detected in lymphocytes. This isoquinoline induced apoptotic DNA damage in human dopaminergic neuroblastoma SH-SY5Y cells. Among catechol is oquinolines, only N-methylsalsolinol induced apoptosis in the cells, and th e scavengers of hydroxyl radicals and antioxidants suppressed DNA damage, s uggesting that reactive oxygen species initiate apoptosis. The isoquinoline activated caspase-3 like proteases and a caspase-3 inhibitor protected the cells from DNA damage. (-)Deprenyl, but neither clorgyline nor pargyline, prevented apoptotic cell death. The mechanism of the protection was due to stabilization of mitochondrial membrane potential reduced by the toxin. In Parkinson's disease apoptosis may be induced in dopamine neurons by this en dogenous neurotoxin, and (-)deprenyl may protect them from apoptotic death process.